The overarching goal of this project is to identify hypothalamic-pituitary-adrenal (HPA)-axis-related[unreadable] parameters as potential predictors and/or biomarkers of disease progression and response to treatment for[unreadable] major depression in treatment-naTve patients. We will develop candidate parameters related to the HPA-axis,[unreadable] and more specifically, to glucocorticoid receptor (GR) function. Those parameters may include genotypes or[unreadable] haplotypes at GR-related loci, differences in expression of GR chaperone genes, measurements of GR[unreadable] function in vivo and in vitro, or some combination of these. Once our genetic investigations have identified[unreadable] putative predictors of treatment response, they will be integrated with data from neuro-imaging, transporteroccupancy[unreadable] studies, clinical assessments and other data for inclusion in an overall model of response[unreadable] predictors to be developed in the Special Scientific Procedures Core.[unreadable] The specific aims of this project include examination of relationships among HPA-axis-associated[unreadable] markers, measured at the genotypic, mRNA-expression, biochemical and systemic levels. More specifically[unreadable] we will investigate how sequence variation at the genetic level in GR receptor- regulating genes associate[unreadable] with mRNA expression in monocytes isolated from patients at multiple timepoints, and to glucocorticoid[unreadable] receptor function measured in vitro (i.e., in monocytes) as well as in vivo (using the combined[unreadable] dexamethasone suppression/CRH stimulation (DEX-CRH) test).[unreadable] Integrating multiple levels of analysis may help to identify genetic and molecular mechanisms for HPAaxis[unreadable] dysregulation and its normalization in response to anti-depressant treatment, thereby suggesting[unreadable] specific predictors for response to antidepressant treatments or disease progression. The elucidation of[unreadable] molecular mechanisms for the normalization of HPA-axis hyperactivity that accompanies successful[unreadable] antidepressant treatment may also be an important step in the development of novel antidepressants.[unreadable] This project will interact closely with the Operations and Clinical Assessment Core by coordinating all[unreadable] necessary blood draws and endocrine challenge tests and through a shared database integrating genetic[unreadable] and phenotypic data, the Research Methods Core by genotyping polymorphisms in all candidate genes[unreadable] relevant for this project and providing detailed information on their population-specific haplotypic structure,[unreadable] and the Special Scientific Procedures Core by generating multi-level HPA-axis related data for inclusion in[unreadable] the overall predictive model for treatment outcome.